In the central nervous system of the mammals, including human, there are three kinds of benzodiazepine (hereinafter, occasionally referred to as BZ) recognition sites, and each is named as central-type (.omega..sub.1, .omega..sub.2) benzodiazepine receptors and a peripheral-type (.omega..sub.3) benzodiazepine receptor, respectively (hereinafter, occasionally referred to as BZ.omega..sub.1 -receptor, BZ.omega..sub.2 -receptor and BZ.omega..sub.3 -receptor, respectively). Among them, the peripheral-type BZ-receptor unevenly distributes in the peripheral tissues or organs such as kidney, liver, heart, etc., but it especially distributes with high density in the cells of the endocrinium organs such as adrenal glands, testicles, etc., or in the cells deeply participating in the inflammation-immune system in whole body such as mast cells, lymphocytes, macrophages, blood platelets, etc., so that the physiological roles of the peripheral-type BZ-receptor have recently been drawing attention.
On the other hand, the peripheral-type BZ-receptor is present a lot in the mitochondrial membrane of glial cells in the brain, and it participates in cholesterol influx into the mitochondrial membrane, and hence, it is thought to act on the biosynthesis pathway of cholesterol into neurosteroids such as allopregnanolone, allotetrahydrodeoxycorticosterone (THDOC), etc. via pregnenolone. Thus, it is considered that stimulation of the peripheral-type BZ-receptor accelerates the synthesis of neurosteroids in the brain which affect the choride ion channel gating process by binding to the neurosteroid-specific recognition site on the .gamma.-aminobutyric acid-A-receptor (hereinafter, occasionally referred to as GABA.sub.A -receptor) [cf. Romeo, E., et al., J. Pharmacol. Exp. Ther., 262, 971-978 (1992)].
A compound having a non-BZ nucleus and selectively showing an affinity for the peripheral-type BZ-receptor has been disclosed in Japanese Patent First Publication (Kokai) No. 201756/1983 (EP-A-94271), and since then, various compounds are disclosed in many literatures including patent applications. However, there is no compound which has actually been used as a medicament.
As a compound having a non-BZ nucleus and selectively showing an affinity for the peripheral-type BZ-receptors, in addition to the above, there have been known the compounds disclosed in Japanese Patent First Publication (Kokai) Nos. 5946/1987 and 32058/1990.
Japanese Patent First Publication (Kokai) No. 5946/1987 (EP-A-205375, U.S. Pat. No. 4,788,199) discloses amide compounds of the following formula, which are bound to the peripheral-type BZ-receptor, and are useful as anxiolytics, anticonvulsants and antiangina agents, and for the treatment of immuno-deficiency syndrome. ##STR2## wherein A is a nitrogen atom or .dbd.CH--; B is a nitrogen atom or .dbd.CH--; V and W are the same or different and each a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group both having 1 to 3 carbon atom, etc.; Z is bound in the ortho- or para-position with respect to the B, and is a phenyl group, a thienyl group, a pyridyl group, or a phenyl group substituted by 1 to 2 groups selected from a halogen atom, an alkyl group or an alkoxy group both having 1 to 4 carbon atoms, trifluoromethyl group and a nitro group; a chain of --X--(CH.sub.2).sub.n --(CHR).sub.m --CONR.sub.1 R.sub.2 is bound in the ortho- or para-position with respect to the B; R is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; R.sub.1 and R.sub.2 are the same or different and each a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group, a phenylalkyl group or a cyclo-alkylalkyl group wherein the alkyl moiety has 1 to 3 carbon atoms and the cycloalkyl moiety has 3 to 6 carbon atoms, or an alkenyl group having 3 to 6 carbon atoms wherein the double bond is not located at the 1,2-position with respect to the nitrogen atom, and R.sub.1 and R.sub.2 may combine together with the nitrogen atom to which they are attached to form pyrrolidine, piperidine, morpholine or thiomorpholine ring; X is --CHR.sub.3 --, --NR.sub.4 --, --SO--, --SO.sub.2 --, an oxygen atom or a sulfur atom; R.sub.3 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; R.sub.4 is an alkyl group having 1 to 3 carbon atoms; m is 0 or 1; and is 0, 1 or2,
provided that when X is --SO--, --SO.sub.2 -- or --NR.sub.4 --, the total number of m+n should be at least 1, and that when both of A and B are a nitrogen atom and Z is at the para-position with respect to the B, X should not be --CHR.sub.3 --, and that when A is .dbd.CH--, B is a nitrogen atom, Z is in the ortho-position with respect to the B, X is an oxygen atom and R is a hydrogen atom, the total number of m+n is other than 1, and excluding 2-phenyl-4-quinolyl-N,N-dimethylcarbamate.
Japanese Patent First Publication (Kokai) No. 32058/1990 (EP-A-346208, U.S. Pat. No. 5026711) discloses that 4-amino-3-carboxyquinoline compounds of the following formula show an affinity for the peripheral-type BZ-receptor both in vivo and in vitro, and can be used in the prophylaxis or treatment of human cardiovascular diseases, or as an antiallergic agent, or in the prophylaxis or treatment of infectious diseases, or in the treatment of anxiety. ##STR3## wherein R.sub.1 and R.sub.2 are each a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, or a C.sub.2 -C.sub.6 alkenyl group, a phenyl group or a benzyl group, or R.sub.1 and R.sub.2 may combine together with the nitrogen atom to which they are attached to form a C.sub.4 -C.sub.8 saturated heterocyclic group; R.sub.3 is a hydrogen atom, a C.sub.1 -C.sub.6 alkyl group, a phenyl group or a C.sub.7 -C.sub.9 phenylalkyl group; R.sub.4 is a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group; R.sub.5 and R.sub.6 are each a hydrogen atom, a halogen atom, a C.sub.1 -C.sub.3 alkyl or alkoxy group, a nitro group, or a trifluoromethyl group, or combine together to form a methylenedioxy group; Z is OR.sub.7 (R.sub.7 is a hydrogen atom or a C.sub.1 -C.sub.6 alkyl group), NR.sub.8 R.sub.9 (R.sub.8 and R.sub.9 are each a hydrogen atom, a C.sub.1 -C.sub.4 alkyl group, a phenyl group or a benzyl group), a C.sub.1 -C.sub.4 alkyl group, a benzyl group, a C.sub.4 -C.sub.6 aryl group which may optionally have a heteroatom; R.sub.10 is a hydrogen atom, a C.sub.1 -C.sub.4 alkyl group or a phenyl group (provided that when Z is not a benzyl group or an aryl group, R.sub.3 is not a hydrogen atom, and a phenyl group and a benzyl group may optionally be substituted by a halogen atom, a C.sub.1 -C.sub.3 alkoxy, alkyl or thioalkyl group, a nitro group, a trifluoromethyl group or a hydroxy group, and these alkyl and alkoxy groups are straight chain, branched chain or cyclic ones, respectively); n is 0, 1 or 2; p is 0 or 1; one of A, B, C and D is N, and the other ones are each CH, or all A, B, C and D are each CH.
On the other hand, there are known some acetamide derivatives having a 2-phenyl-4-pyrimidinylamino moiety. For example, U.S. Pat. No. 3,631,036 discloses some compounds represented by 2-(5-cyano-2-phenyl-4-pyrimidinyl-amino) acetamide as a synthetic intermediate for 5-amino-2,6-di-substituted-7H-pyrrolo[2,3-d]pyrimidines. U.S. Pat. No. 3,631,045 discloses some compounds represented by 2-(5-cyano-6-methylamino-2-phenyl-4-pyrimidinylamino)-acetamide as a synthetic intermediate for 4,5-diamino-7H-pyrrolo[2,3-d]-pyrimidines. However, the pharmacological activities of these compounds have never been disclosed yet.
Besides, Pharmazie, 43, 537-538 (1988) discloses some compounds represented by 2-(5-acetyl-6-methyl-2-phenyl-4-pyrimidinylthio)-N-(4-chloro-phenyl) acetamide and 2-(5-acetyl-6-methyl-2-phenyl-4-pyrimidinylthio)-N-(4-methylphenyl) acetamide, as a synthetic intermediate for thieno[2,3-d]pyrimidine derivatives. Moreover, it is also disclosed in said literature that 2-(5-acetyl-6-methyl-2-phenyl-4-pyrimidinylthio)-N-(4-chlorophenyl)acetami de shows antibacterial activity against Bacillus subtilis.